Choline sulfonate derivatives

ABSTRACT

Choline sulfonate derivatives, characterized by the activating effect on digestive function and having stability against moisture, are produced by reacting Alpha -alkanoyloxy- Alpha alkyl-acetic acid dimethylaminoethyl esters with methyl sulfonates.

United States Patent [1 1 Miura et a1. Sept. 2, 1975 1 CHOLINE SULFONATE DERIVATIVES [58] Field of Search 260/484 A [75] Inventors: Koji Miura, Kanazawa; Noboru Takagawa, Toyama; Yasuyuki [56] References C'ted Suzuki, Toyama; Yuji Matsumoto, Toyama. all of Japan Assignee: Toyama Chemical Co., Ltd., Tokyo,

Japan Filed: May 31, 1974 Appl. No.: 475,048

Foreign Application Priority Data June 12, 1973 Japan 48-65331 June 20, 1973 Japan 48-68724 US. Cl. 260/484 A; 260/484 R Int. Cl. C07C 69/66 FOREIGN PATENTS OR APPLICATIONS 1,336,350 7/1973 United Kingdom 260/484 A Primary E.\-aminerAnton H. Sutto Assistant Examiner P. J. Killos Attorney, Agent, or FirmBierman and Bierman 5 7 ABSTRACT 11 Claims, N0 Drawings CHOLINE SULFONATE DERIVATIVES This invention relates to choline sulfonate derivatives and to a process for preparing them.

Heretofore Applicants found that the compounds of 5 (Ill) (cH,l,NcH,cH,ococH-R. (n

l ocoR,

in which R is lower alkyl, R is methyl and X is halogen.

However, these compounds (I) are susceptible to decomposition due to moisture absorption. These compounds are found to be strongly hygroscopic whether in tablet form or other dosage forms.

As a result of additional research, it was found that novel choline compounds (11) could be obtained. These OCOR,

in which R and R are individually lower alkyl, R is a sulfonate and n is l or 2.

It has been found that the compounds of the present 10 invention may be prepared by any one of the methods A, B and C described below.

Process A G 6-) O [(cup Ncl-l cmon] R; [(cHmNcmci-ipcocHR, R

OCOR,

[mpncov] ocoR (IV) (ll) Y represents a reactive group as defined below and R R R and n are the same as defined above. Hence, the choline sulfonate derivatives (11) of the present invention are obtained by reacting choline sulfonates (111) with reactive derivatives (IV) of -alkanoyloxy--alkylacetic acid such as those exemplified below.

Process B OCOR R R R and n are the same as defined above.

Hence, the choline sulfonate derivatives (11) of the present invention are obtained by reacting alkanoyloxy--alkyl-acetic acid dimethylaminoethyl espossess less hygroscopicity and increased stability when 40 ters (V) with methyl sulfonates (V]) prepared in dosage form, as well as at least equivalent pharmacological effects when compared with the pre- Process C m RzCOY) o (CH3)3NCHCH,OCOCHR| R. (CH )=NCH,CH,OCOtiJHR, R,

, ocoR vious compound (I). These results are most surprising,

especially in view of the fact that they are obtained merely by replacing the substituent X in compound (I).

An object of this invention is to provide a novel compound (ll) possessing strong effects in activating digest ing function.

Another object of this invention is to provide a novel apparent from the specification and accompanying examples.

Briefly stated. the present invention comprises a novel choline sulfonate derivative of the formula (11):

(Vlll) R R R;;, n and Y are the same as defined above.

Hence, the choline sulfonate derivatives (11) of the present invention are obtained by reacting -hydroxy-- alkyl-acetic acid trimethylammoniumethyl ester sulfonates (Vll) with a reactive derivative (VIII) of a carboxylic acid. The symbols R and R of the compounds of formulas (I1), (1V), (V), (Vll) and (VIII) include lower alkyl, such as methyl, ethyl, propyl, butyl, pentyl and their isomers. The symbol R of the compounds of the formulas (11), (111), (VI) and (VII) signifies monosulfonates or di-sulfonates. The mono-sulfonates include. for example, aryl sulfonates such as benzene sulfonate, toluene-2-sulfonate, toluene-4-sulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, camphor3-sulfonate, camphor-S-sulfonate, camphor-lO- sulfonate, and the like. The disulfonates include, for example, aryl di-sulfonates such as benzene-l,3-disulfonate, toluene-3,5-disulfonate, naphthalene-l,5- di-sulfonate, naphthalene-2,o-di-sulfonate, and naphthalene-2,7-di-sulfonate. The above aryl groups can be substituted by one or more of substituents such as nitro, alkyl, or halogen etc.

Suitable reactive derivatives corresponding to the compound of formula (IV) and (VIII) include, for ex ample, acyl halides, acid anhydrides, or the mixed acid anhydrides with another acid such as toluene-4- sulfonic acid, or ethyl chlorocarbonate. Hence the term Y as used above represents an acyl substituent which would be reactive with the l-ethyl hydroxy group of compounds (III) or the -hydroxy group of compound (VII), thus forming the compound (II) of the present invention. Such acyl substituents are well recognized in the art and include such acyl substituents as halide, anhydride, and other acyl substituents such as p-toluene sulfonate and ethylchlorocarbonate.

Moreover, the choline sulfonate derivatives of the compound of formula (III) to be used as the starting material of method A is easily obtained by reacting dimethylaminoethanol with methyl sulfonates (VI).

Additionally, the -alkanoyloxy--alkyl-acetic acid dimethylaminoethyl ester of the compound of formula (V) to be used as the starting material of method 8 is easily obtained by reacting dimethylaminoethanol with -alkanoyloxy--alkylacetyl halides.

Additionally, the hydroxy--alkyl-acetic acid trimethylammoniumethyl ester sulfonate corresponding to the compound of formula (VII) is easily obtained by reacting -hydroxy--alkyl-acetic acid dimethylaminoethyl esters with methyl sulfonates (VI).

The present invention comprises providing a novel compound possessing strong effects for activating the digesting function as well as less hygroscopicity than the known choline compounds and an improved preparation of the compound of formula (II).

In carrying out process A, the compounds of formulas (III) and (IV) are reacted in an inert solvent while heating. Alternatively, the compound of the formula (III) is dissolved in an excess amount of the compound of the formula (IV) and reacted at elevated temperatures.

Examples of inert solvents to be employed in the present invention are chloroform, dioxane, acetone, and acetonitrile. Reaction temperatures of from about 50C to 100C are suitable, as are reaction times of about 2 to hours. After the completion of the reaction, the reaction mixture is allowed to stand at room temperature in order to permit crystallization to occur. Thus, the desired product (II) is obtained in the form of crystals by filtration or other separation means.

In carrying out process B, the compounds of formulas (V) and (VI) are mixed and reacted in the presence or absence of an inert solvent. As an inert solvent, for example, it is preferred to use ethers, ketones, alcohols,

and hydrocarbons and the reaction is conducted at a temperature in the range of about 20 to C for about 1 to 2 hours. When the reaction is complete, the reaction mixture is allowed to stand at room temperature to permit crystallization of the product: The product crystals are recovered by filtration of the deposited crystals or by other conventional separation means.

In addition to the above, in carrying out process C, the compounds of formulas (VII) and (VIII), are dissolved in the presence of the inert solvent, or the compound of the formula (VII) is dissolved in a stoichiometric excess amount of the compound of formula (VIII) and is reacted to form the product (II). Alternatively, an organic base such as pyridine or triethyl amine can be added. As inert solvents, chloroform, dioxane, acetone, acetonitrile and the like are preferred. The preferred temperature range is about 50 to 100C. After the reaction, the reaction mixture is allowed to stand at room temperature in order to permit crystallization of the product.

When the reaction is conducted using an excess amount of the compound of the formula (VIII), after completion of the reaction, diethylether is added to the reaction mixture and excess amounts of the compound of the formula (VIII) and by-products formed in the reaction are thus extracted.

After extraction the residual solution is allowed to stand while cooling. Crystals of the desired product (II) then separate out. Thus, pure crystals of the desired product (II) are obtained and are separated by filtration or other recognized means.

The product (II) which is obtained by methods A, B or C of the present invention is of a high purity. Even higher purities are obtainable by recrystallization from solvents such as acetone or ethyl alcohol or mixtures of such solvents.

Additionally, in carrying out the processes A, B, and C of the present invention, it should be understood that the preferred reaction conditions and the manner of posttreatment are not limited by the foregoing descriptions. Hence, optimization of these parameters can easily be determined by a person of reasonable skill with respect to the particular reagents and solvents employed.

According to the present invention, it is now possible to obtain the novel compounds of the formula (II) possessing the aforesaid advantages and to prepare them.

The pharmacological effect, toxicity and stability [appearance, hygroscopic property and rate of decomposition] of the products (II) of the present invention will now be described as follows:

A. Activity of miceisolated ileum and hygroscopic properties:

Table l (CH;.);NCH,CHOCOCHR, R 6

OCOR,

Hygroscopic property Specific Variables Activity on mice Rate of isolated ileum Exterior moisture absorption No. R R R1 n 17 CH CH Cl 1 -lH-l deliquesccnce 20.0%

H S0 2. CH CH; l -+H partial 5.0%

-IH- deliqucscencc Table l-continued tcu mcu cuococlua. R

OCOR,

Hygroscopic property Specific Variables Activity on mice Rate of isolated ileum Exterior moisture absorption No R R 3 n 503 3. CH CH l +l-H- stability 0.2%

4. CH CH 1 -H++ 01% s. CH: CH, a l 4-H- 0.4%

6. CH CH 2 +i-H- 0.07%

S 7. CH CH w a z -H-++ 0.7%

S0 2;. CH, C H, 1 0.5%

S0 9. CH C 11 l 4-H- 0.6%

10 CH; CZHS 2 +H+ 0.3%

The contractive ratio in a concentration of 1 V4 10 g/ml of each drug. A ratio of 100% is deemed to be the ileum contraction from 1 V4 [0" g/ml of acetylcholine chloride,

8O 7r -H-H- The variation in weight after standing for 24 hours at a moisture of 80%. relative humidity at l8C. -a :etmtymethyl acetylcholine chloride B. Activity on mice-isolated ileum and stimulous action of small intestine and stomach of guinea pig in vivo. 60

Table ll Drug Activity on mice Stimulous action of Stimulous action of No. isolated ileum the small intestine stomach of guinea pig of guinea pig in vivo" in vivo" l m l l gl glP o.) l l g/ g(P.O.)l

Ach"' I50 noneffectivc I50 non-effective l 1.06 V4 I0" effective ISO efficacy 4 L40 V4 10' l50 effective l50 efficacy 7 8 Table ll-continued Drug Activity on mice Stimulous action of Stimulous action of No. isolated ileum* the small intestine stomach of guinea pig of guinea pig in vivo** in vivo*** D-.0 l l g/ g(P.O-) l [mg/kg(P.O.)]

6 L57 A 10 150 effective 150 efficacy Measured by Magnus Method Pfliigers Arch. Ges. Physiol. 102. 349-363 (1904) Calculated by Comparison with the contract of Ach at 1 V4 7 g/ml concentration as 100%. 7 "Measured by Trendelcnburg Method Z. Biol. 61 67 (l9l3) "Measured by Ballon technique'Carlson. AJ. l9l6). The control of hunger in health and disease. The Univ. of Chicago Press. Chicago. Ach= acetylcholine chloride C. Action to a charcoal passage in gastrointestinal motility of mice and mice acute toxicity.

Table III Drug Action of propulsion Mice acute toxicity No. of a charcoal meal* LD g/kg(P.O.) LD mg/kg(S.C.)

[mg/kg(S.C.)]

2 Ach 30 110% 3 170 0 EXAMPLE 1 l 120% 6.8 576 2 38 i :2 2%; Preparation of -acetoxy--methyl acetic acid 0 trimethylammoniumethyl ester benzene sulfonate Drugs were administered (S.C.) to mice which starved for 17 hrs. After 20 minutes, charcoal suspension was administered and after an additional 20 minutes. of chohne benzene sulfonate (obtalned react intestine was isolated. Ratio of charcoal transferred length to total length ofintesmethyl benzenesulfonate amino ethatine (from Pylorus to Anus) were calculated as compared with a control group which was not administered with the present invention. (Control 100%) was suspenqed ml To thls suspens1on 3.7g of lactic acid anhydride diacetate was added D R f b d d and the mixture solution refluxed for 4 hours. After the T l lj h molsttulie a sorpnon an ecorpposltlon' reaction, the reaction mixture was cooled. 8 ml of die f S enor P F g 0 b f ethyl ether was added and was allowed to stand over- 2 Sorp gg c 5 5 18 mg a ter emg night whereupon crystals separated out. The crystals ept at molsture 0 or were collected by filtration and 3.7g (86% yield) of the Table IV product having a melting point of 96 to 99C were ob- Drug *Rate of moisture Rate of talned' No. absorption decomposition EXAMPLE 2 l deliquescence 30.0 25.0 4 stability 05 Q5 Preparation of -acetoxymethyl acetic acid 6 stablllty trimethylammoniumethyl ester toluene-4-sulfonate g zgzg ayfi 40 3g of choline-to]uene-4-sulfonate (obtained by react- E weight before absorption v. 100 mg methyl p-toluene sulfonate with dimethylammo eth- "Rate of decomposition by method of hydroxylamine of ester anol) were suspended in 15 ml 0f acetone. 4g 0f the (Hesmn Blol: 249 (1949) mixed acid anhydride obtained by reacting acetyl-lactic Rate of Decomposition Absorbance f SamEle acid with ethylchlorocarbonate was added to the sus- Absorbance of standard solution X pension and the mixture was refluxed for 3 hours. After It is clear from the above Tables (I) to (IV) that the compounds of the present invention possess excellent stimulating activity in dilute solutions of about 10 mole concentration. Even if the administered amount is less than the effective amount of Ach, the compounds (ll) show'sufficient effects on both the small intestine and stomach. Moreover, the action of compounds (II) in the propulsion of a charcoal meal is much greater than Ach. The acute toxicity of the compounds (ll) is extremely weak when compared with Ach.

Additionally, -acetoxy--methyl acetylcholine chloride (NO. I), which was previously developed by the present inventors, shows deliquescence and partial decomposition, whereas the compounds (ll) show little deliquescence and are stable. Accordingly, the compounds of this invention activate the digesting function and have enhanced stability and low hygroscopic properties.

The following examples are given to more fully illustrate the present invention. The examples are for illustrative purposes only and are not meant to limitthe in-' vention in any way.

the reaction, the resultant solution was cooled to room temperature. The solvent was removed under reduced pressure and the precipitated crystals were collected by filtration. 3. lg yield) of product having a melting point of 106 to 109C were obtained. These crystals were recrystallized from acetone, yielding purified crystals having a melting point of 108 to 1 10C.

EXAMPLE 3 Preparation for -acetoxy--methyl acetic acid trimethylamrnoniumethyl ester-DL-camphorl O-sulfonate 3.3g of choline-DL-camphor-l0-sulfonate were suspended in 10 ml of acetone. To the suspension 3.8 g of lactic acid anhydride diacetate were added and the mixture was refluxed for 3 hours. The reaction mixture was then cooled to room temperature. The solvent was removed under reduced pressure. Subsequently 8 ml of ethyl acetate were added and allowed to stand overnight whereupon product crystals separated out. The separated crystals were collected by filtration.

3.5 g (78% yield) of product having a melting point of 153 to 156C were obtained.

EXAMPLE 4 Preparation of Bi s [-acetoxy--methyl acetic acid trimethylammoniumethyl ester]-naphthalene-l ,S-disulfonate 5.2g of bis(choline)-naphthalene-l ,S-disulfonate was suspended in 30 ml of acetonitrile, and 10 g of lactic acid anhydride diacetate was added thereto. This mixture was refluxed for 3 hours. The resulting reaction mixture was allowed to stand at room temperature while cooling to precipitate thedesired product crystals, which were collected by filtration. 5.5 g (76% yield) of the desired product having a melting point of 189 to 191C were obtained.

EXAMPLE 5 Preparation of -butyryloxy--methyl acetic acid trimethylammoniumethyl ester toluene-4-sulfonate 3 g of choline-to]uene-4-sulfonate were suspended in 8 ml of dioxane. 2g of butyryl lactoyl chloride were added to the suspension and reacted for 2 hours at 80C. After the reaction, the reaction solution was cooled to room temperature and the solvent removed under reduced pressure. To the residue thus obtained, 8 ml of diethyl ether was added and the mixture was allowed to stand overnight to precipitate product crystals. 3.3 g (72% yield) of the desired product having a melting point of 91 to 94C were obtained.

EXAMPLE 6 Preparation of -acetoxy-me thyl acetic acid trimethylammoniumethyl ester toluene- 4-sulfonate 3 g of choline-p-toluene sulfonate were suspended in ml of acetone and the mixed acid anhydride obtained from 1.5 g of acetyl lactic acid, 2.2 g of ptoluene sulfonyl chloride and 1.5 g of triethyl amine was added thereto and reacted for 1 hour at 50 to 60C. Subsequently, 30 ml of diethylether were added to the reaction mixture in order to dissolve the soluble substances. The ether layer was removed to obtain the oily residue. The oily residue was allowed to stand overnight at room temperature in order to form product crystals. 2.5 g (61% yield) of high purity product having a melting point of 109 to 1 10C was obtained by recrystallizing the product crystals from acetone.

EXAMPLE 7 Preparation of -acetoxy methyl acetic acid trimethylammoniumethyl ester benzenesulfonate 5 g of -acetoxy--methylacetic acid dimethylamino ethyl ester were dissolved in 20 ml of acetone, and 4.3 g of methyl benzene sulfonate were added thereto. The reaction was exothermic. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration. 8.8 g (95% yield) of the desired product having a melting point of 100 to 103C were obtained.

EXAMPLE 8 Preparation of -acetoxy--methylacetic acid trimethylammoniumethyl ester toluene-4-sulfonate 20 g of -acetoxy--methylacetic acid dimethylaminoethyl ester were dissolved in 30 ml of acetone. 19 g of methyl-p-toluene sulfonate were gradually added thereto while cooling. The reaction was exothermic. The resultant reaction mixture was allowed to stand for 10 cooling so as to precipitate product crystals. 3.6 g (90% yield) of the desired product having a melting point of 108 to 1 10C were obtained by filtration. Recrystallization from acetone yielded product crystals melting at 109 1 10C.

EXAMPLE 9 Preparation of -acetoxy-methylacetic acid trimethylammoniumethyl ester-DL-camphorl 0-sulfonate 5 g of methyl-DL-camphor-10-sulfonate were dissolved in 20 ml of ethylacetate, and 4 g of -acetoxy-- methyl acetic acid dimethylaminoethyl ester were added thereto and reacted at 50 to 60C for 10 minutes.

After the reaction, the solution was allowed to cool whereupon product crystals precipitated. 7.5 g yield) of the desired product having a melting point of I53 to 156C were obtained by filtering the deposited crystals.

EXAMPLE [0 Preparation of -acetoxy--methyl acetic acid trimethylammoniumethyl ester naphthalene-Z-sulfonate 2.2 g of methyl-naphthalene-2-sulfonate were dissolved in 10 ml of ethyl acetate and 2 g of -acetoxy-- methyl-acetic acid dimethylaminoethyl ester were added thereto and reacted at 50 to 60C for 10 minutes.

After the reaction, the reaction solution was allowed to cool so as to precipitate product crystals. Filtration yielded 3.l g (70%) of the desired product having a melting point of to 96C. Recrystallization from ethyl acetate yielded pure product having a melting point of 94 to 97C.

EXAMPLE 11 Preparation of Bis[-acetoxy--methyl-acetic acid trimethylammoniumethyl esterl-naphthalene-l ,S-disulfonate 5 g of methyl-naphthalene-l,S-disulfonate were suspended in 40 ml of acetonitrile and 6.5 g of -acetoxy-- methyl-acetic acid dimethylaminoethyl ester was added thereto. The solution was heated for 30 minutes at 50 to 55C. After the reaction, the mixture was allowed to cool so as to precipitate product crystals. Filtration yielded 10 g (87%) of the desired product having a melting point of 189 to 191C.

EXAMPLE 12 Preparation of Bis[-acetoxy--methyl-acetic acid trimethylammoniumethyl ester]-naphthalene2,6-disulfonate.

5 g of methyl-naphthalene-Z,6disulfonate were suspended in 40 ml of acetonitrile, and 6.5 g of -acetoxy-- methyl-acetic acid dimethylaminoethyl ester was added thereto. Subsequently the reaction and post-treatment were conducted under the same conditions of example 6. and 10.5 g (9l%) of the desired product having a melting point of 227 to 230C were obtained. When this was recrystallized from methyl alcohol, there was obtained a pure product having a melting point of 228 to 230C.

EXAMPLE 13 Preparation of Bis[-propionyloxy--methyl acetic acid trimethylammoniumethyl ester]-naphthalene-l ,S-disulfonate 3g of methyl-naphthalene-l,S-disulfonate were suspended in 20 ml of ethyl alcohol, and 4 g of propionyloxy--methyl-acetic acid dimethylaminoethyl ester was added thereto. The ensuing reaction proceded for 30 minutes at 40 to 50C, and then ml of ether were added. The reaction solution was allowed to stand overnight to precipitate product crystals. 5.8 g

(85% yield) of the desired product having a melting point of 120 to 123C were obtained by filtering off the precipitated crystals. I

EXAMPLE 14 Preparation of -propionyloxy--methyl-acetic acid timethylammoniumethyl ester 'toluene-4-sulfonate To 5 g of-hydroxy--methyl-acetic acid trimethylammoniumethylester toluene-4-sulfonate having a melting point of 106 to 108C. (obtained by reacting dimethyl amino ethyl lactate with methyltoluene-4-sulfonate) was added 15 ml of propionic anhydride and 1 m1 of pyridine. This mixture was reacted at 100C for 3 hours. Afterthe reaction, the reaction solution was allowed to cool. Subsequently 30 ml of diethyl ether were added in order to extract the impurities from the reaction solution. The ether layer was removed, leaving an oily residue. The thus obtained oily residue was allowed to stand overnight at about DC in order to obtain 4.8 g (83% yield) of crude product having a melting point of 84 to 88C. When this was recrystallized from ethyl acetate, the purified crystals melted at 87 to 90C.

EXAMPLE 15 Preparation of -butyryloxy--methyl-acetic acid trimethylammoniumethyl ester toluene-4-sulfonate To 5 g of -hydroxy--methyl-acetic acid trimethylammoniumethyl ester toluene-4-sulfonate was added 15 ml of butyric anhydride and l ml of pyridine. Subsequently the reaction and post-treatment were conducted under the same conditions as in example 8, and there was obtained 4.7 g (79%) of the, desired product having a melting point of to 97C.

What is claimed is:

l. A choline sulfonate derivative of the formula coR in which R and R individually, are lower alkyl, R is aryl sulfonate, camphor sulfonate, or aryl di-sulfonate and n is l or 2.

'2. The choline sulfonate derivative of claim 1 in which R is benzene sulfonate, toluene sulfonate, naphthalene sulfonate, or naphthalene di-sulfonate.

3. The derivative of claim 1 in which -R and R are methyl, R is benzene sulfonate and n is 1.

4. The derivative of claim 3 in which R is p-toluene sulfonate.

5. The derivative of claim 3 in which R is camphorlO-sulfonate.

6. The derivative of claim 3 in which R is naphthalene- 2-sulfonate.

7. The derivative of claim 3 in which R is naphthalene-l ,5-disulfonate and n is 2.

8. The derivative of claim 3 in which R is naphthalene-2,6-disulfonate and n is 2.

9. The derivative of claim 1 in which R is ethyl, R is methyl, R is naphthalene-l ,S-disulfonate and n is 2.

10. The derivative of claim 9 in which R is p-toluene sulfonate and n is l.

11. The derivative of claim 4 in which R is propyl. 

1. A CHOLINE SULFONATE SULFONATE DERIVATIVE OF OF THE FORMULA
 2. The choline sulfonate derivative of claim 1 in which R3 is benzene sulfonate, toluene sulfonate, naphthalene sulfonate, or naphthalene di-sulfonate.
 3. The derivative of claim 1 in which R1 and R2 are methyl, R3 is benzene sulfonate and n is
 1. 4. The derivative of claim 3 in which R3 is p-toluene sulfonate.
 5. The derivative of claim 3 in which R3 is camphor-10-sulfonate.
 6. The derivative of claim 3 in which R3 is naphthalene-2-sulfonate.
 7. The derivative of claim 3 in which R3 is naphthalene-1,5-disulfonate and n is
 2. 8. The derivative of claim 3 in which R3 is naphthalene-2,6-disulfonate and n is
 2. 9. The derivative of claim 1 in which R1 is ethyl, R2 is methyl, R3 is naphthalene-1,5-disulfonate and n is
 2. 10. The derivative of claim 9 in which R3 is p-toluene sulfonate and n is
 1. 11. The derivative of claim 4 in which R2 is propyl. 